Abstract
Emerging and re-emerging zoonotic viruses, including Nipah virus, Lassa virus, and rabies virus, represent a persistent and escalating threat to global public health, for which no broadly effective antiviral agents currently exist. Metadichol®, a nanoemulsion of long-chain alcohols (policosanol), has previously demonstrated significant in vitro efficacy against diverse viruses including severe acute respiratory syndrome coronavirus 2 and Ebola virus. In this study, we present new in vitro data showing that Metadichol potently inhibits Lassa, Nipah, and rabies virus entry using a novel alphavirus-based pseudovirus platform, with half-maximal inhibitory concentration values of 831.7, 2455, and 2621 ng/mL, respectively, and no significant cytotoxicity in human embryonic kidney 293T cells.
We focus our mechanistic analysis on two core pathways that underpin this broad-spectrum activity. First, we describe the vitamin D receptor–MYC–specificity protein 1–G1 to S phase transition 1 axis, in which Metadichol activates the vitamin D receptor, leading to MYC-mediated repression of specificity protein 1 and consequent downregulation of G1 to S phase transition 1 (also known as eukaryotic release factor 3a), a translation termination factor recently validated as a druggable host dependency factor essential for the replication of Lassa, Ebola, and other viruses. Second, we examine Metadichol’s modulation of nuclear receptors—including neuron-derived orphan receptor 1, liver X receptor alpha, and peroxisome proliferator-activated receptor gamma—which suppress interferon regulatory factors and the interferon-beta promoter, thereby fine-tuning the innate immune response to prevent immunopathology while maintaining antiviral defense.
Together, these two mechanisms—direct replication blockade via G1 to S phase transition 1 inhibition and immune optimization via nuclear receptor modulation—provide a mechanistic framework for Metadichol’s observed broad-spectrum efficacy. Given that Metadichol is commercially available and non-toxic (median lethal dose > 5000 mg/kg in rats), these findings support its further clinical investigation as a host-directed antiviral agent.